Multi-omic profiling reveals associations between the gut mucosal microbiome, the metabolome, and host DNA methylation associated gene expression in patients with colorectal cancer

Qing Wang,Qiangqiang Wang,Yating Li,Xiaoyuan Bian,Jingjing Wu,Mark P Hodson,Eleni Giannoulatou,Lanjuan Li,Loïc M Thibaut,Kaicen Wang,Longxian Lv,Wenrui Wu,Liya Yang,Ding Shi,Jianzhong Ye,Daiqiong Fang,Xianwan Jiang,Joshua W K Ho

doi:10.1186/s12866-020-01762-2

Abstract

BackgroundThe human gut microbiome plays a critical role in the carcinogenesis of colorectal cancer (CRC). However, a comprehensive analysis of the interaction between the host and microbiome is still lacking.ResultsWe found correlations between the change in abundance of microbial taxa, butyrate-related colonic metabolites, and methylation-associated host gene expression in colonic tumour mucosa tissues compared with the adjacent normal mucosa tissues. The increase of genus Fusobacterium abundance was correlated with a decrease in the level of 4-hydroxybutyric acid (4-HB) and expression of immune-related peptidase inhibitor 16 (PI16), Fc Receptor Like A (FCRLA) and Lymphocyte Specific Protein 1 (LSP1). The decrease in the abundance of another potentially 4-HB-associated genus, Prevotella 2, was also found to be correlated with the down-regulated expression of metallothionein 1 M (MT1M). Additionally, the increase of glutamic acid-related family Halomonadaceae was correlated with the decreased expression of reelin (RELN). The decreased abundance of genus Paeniclostridium and genus Enterococcus were correlated with increased lactic acid level, and were also linked to the expression change of Phospholipase C Beta 1 (PLCB1) and Immunoglobulin Superfamily Member 9 (IGSF9) respectively. Interestingly, 4-HB, glutamic acid and lactic acid are all butyrate precursors, which may modify gene expression by epigenetic regulation such as DNA methylation.ConclusionsOur study identified associations between previously reported CRC-related microbial taxa, butyrate-related metabolites and DNA methylation-associated gene expression in tumour and normal colonic mucosa tissues from CRC patients, which uncovered a possible mechanism of the role of microbiome in the carcinogenesis of CRC. In addition, these findings offer insight into potential new biomarkers, therapeutic and/or prevention strategies for CRC.

Highlights

The human gut microbiome plays a critical role in the carcinogenesis of colorectal cancer (CRC)
Comparison of microbial composition between tumour and adjacent normal tissues Non-metric multidimensional scaling (NMDS) analysis based on the unweighted UniFrac distance on operational taxonomic units (OTUs) revealed that the microbial community composition of the cancerous tissues could be clearly distinguished from the non-cancerous tissues, which was confirmed by analysis of similarities (Anosim) (p-value = 0.002; Fig. 1a)
There was an under-representation of Bacteroidaceae, Lachnospiraceae and Ruminococcaceae and predominance of Fusobacteriaceae in tumour tissues (p-value > 0.05)

Summary

Introduction

The human gut microbiome plays a critical role in the carcinogenesis of colorectal cancer (CRC). A comprehensive analysis of the interaction between the host and microbiome is still lacking. Diet plays an important role in the initiation, promotion and progression of colon carcinogenesis [2]. Diet has been shown to have a dominant impact on the structure and composition of the gut microbiome, microbial generated metabolites and host metabolism [5, 6]. Many studies have demonstrated the effect of the gut microbiome on the pathogenesis of CRC, revealing potential pathogenic bacteria such as Fusobacterium as well as beneficial bacteria such as Lactobacillales [6,7,8]

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Discussion

Conclusion